1. Field of the Invention
The present invention relates to a composition comprising Horse chestnut extract having anti-angiogenic and matrix metalloproteinase inhibitory activity for the prevention and treatment of diseases caused by abnormal angiogenesis and its use thereof.
2. General Background and State of the Art
Angiogenesis is the process of generating new capillary blood vessels. Neovascularization is tightly regulated, and activation occurs in embryogenic development, tissue remodeling, wound healing and periodic cycles of corpus luteum development (Folkman and Cotran; Int. Rev. Exp. Pathol., 16, pp207-248, 1976).
Vasculogenesis means the formation of new endothelial cell during the embryogenesis in order to supply the nutrient for rapidly growing fetus. On the contrary, capillary blood vessel endothelial cells are started to proliferate from existing vasculature in angiogenesis. The endothelial cells are growing very slowly as compared with other types of cells in the body. However, the proliferation of these cells is induced by pro-angiogenic cytokines, inflammation mediators and activated proteolytic enzymes.
By the failure of regulation of angiogenesis, some pathological syndromes are developed (Timar; J. Pathol. Oncol Res., 6, pp85-94, 2001). Pathological angiogenesis is involved in many diseases. For example, cardiovascular diseases such as angioma, angiofibroma, vascular deformity, atherosclerosis, synechia and edemic sclerosis; and opthalmological diseases such as neovascularization after cornea implantation, neovascular glaucoma, diabetic retinopathy, angiogenic corneal disease, macular degeneration, pterygium, retinal degeneration, retrolental fibroplasias, and granular conjunctivitis are diseases related to angiogenesis. Chronic inflammatory diseases such as arthritis; dermatological disease such as psoriasis, telangiectasis, pyogenic granuloma, seborrheic dermatitis and acne are also angiogenesis-dependent diseases.
In particular, angiogenesis is essential to metastasis and growth of cancer (D'Amato R J and Adamis A P, Ophthalmol., 102, pp1261-1262, 1995; Arbiser J L, J. Am. Acad. Derm., 34, pp486-497, 1996; O'Brien K. D. et al.; Circulation, 93, pp672-682, 1996; Hanahan D and Folkman J, Cell, 86, pp353-364, 1996). New blood vessels not only provide nutrients and oxygen to fast-growing cancer cells, but also give ways of entering the blood stream resulting metastasis (Polverini P. J., Critical Reviews in Oral Biology, 6, pp230-247, 1995). Currently, a large variety of chemotherapies and immunotherapies are applied in the treatment of cancer, but the efficacy of the therapies is limited and nothing can successfully extend the life of cancer patients due to the lack of anti-metastasis effects.
Arthritis, a well-known inflammatory disease, is initiated as an autoimmune disease. As the progression of the inflammation, the growth of vascular endothelial cell in the synovial cavity is activated by the cytokines. The cartilage in the articulation is finally destroyed by the formation of articular lamina leak (Kocb A E, et al., Arth. Rheum., 29, pp471-479,1986; Stupack D G, et al.; Braz. J. Med. Biol. Rcs., 32, pp578-581, 1999; Koch A E; Arthritis Rheum., 41, pp951-962, 1998).
Many people are losing their eyesight all over the world because of various ocular diseases. Many patients become blind due to the infiltration of the capillary blood cells into the vitreous humor (Jeffrey M I and Takayuki A, J. Clin. Invest., 103, pp1231-1236, 1999). Therefore, inhibition of angiogenesis is the basic therapeutic modality for these diseases.
Psoriasis is caused by extremely active proliferation of skin cells. Fast-growing cells requires sufficient blood supply, and angiogenesis is abnormally induced in psoriasis (Folkman J., J. Invest. Dermatol., 59, pp40-48, 1972).
Since angiogenesis is closely related to initiation and progression of many diseases, many efforts have been made toward the development of angiogenesis inhibitors in order to prevent and/or treat those diseases.
Not only reorganization of the blood vessel by migration, proliferation and differentiation of endothelial cells, but also degradation of the extracellular matrix is required for angiogenesis. One of the major events for inducing angiogenesis is a breakdown of the extracellular matrix before the formation of the capillary blood vessels. The most important enzyme of matrix degradation is matrix metalloproteinase (MMP), a family of over 20 proteins. MMPs are endopeptidase, which degrade or proteolyze the components of the extracellular matrix such as collagen, proteoglycan, and gelatin, and are classified into four groups: collagenase, gelatinase, stromelysin, and membrane-type MMP. Many enzymes in the MMP family have substrate specificity. The expression of MMP is induced under various physiological circumstances when remodeling of an extracellular matrix is required (Curry T E Jr., Osteen K G; Biol. Repord., 64, pp1285-1296, 2001; Damjanovske S, et al., Ann. NY. Acad. Sci., 926, pp180-191, 2000; Ravanti L, Kahari V M, Int. J. Mol. Med.; 6, pp391-407, 2000).
Increased expression or activation of MMPs is observed in many pathological states, such as atherosclerosis, restenosis, MMP-dependent-osteopathy, inflammation of the central nervous system, Alzheimer's disease, skin aging, rheumatoid arthritis, osteoarthritis, septic arthritis, corneal ulcer, synechia, bone disease, proteinuria, abdominal aortic aneurysm, regressive cartilage loss, myelinated nerve loss, liver fibrosis, nephroglomerular disease, germinal membrane ruptures, inflammatory bowel disease, gingivitis, periodontitis, senile macular degeneration, diabetic retinopathy, proliferate vitreous body retinopathy, immature retinopathy, eye inflammation, conical cornea, Sjogren's syndrome, myopia, eyes tumors, rejection of cornea implantation, angiogenesis and cancer metastasis. (Woessner Jr., Ann. NY. Acad. Sci., 732, pp11-21, 1994; Warner et al., Am. J. Pathol., 158, pp2139-44, 2001; Stetler-Stevenson, Surg. Oncol. Clin. N. Am., 10, pp383-92, 2001).
For example, stromelysins are known to be the major enzyme for disruption of cartilage (Murphy, G. et al., Biochem. J., 248, pp265-268, 1987). Collagenases, gelatinases and stromelysins are responsible for the degradation of the extracellular matrix in many retinopathies (Bruns, F. R. et al., Invest. Opthalmol. and Visual Sci., 32, pp1569-1575, 1989). Collagenases and stromelysins are identified in fibroblast from gingiva in inflammation, and the activity of the enzyme is dependent on the degree of inflammation (Overall, C. M. et al., J Periodontal Res, 22, pp81-88, 1987). MMP activity is highly enhanced in response to the bacterial infection and inflammation in gingival crevicular fluid taken from patients with periodontal disease. Destruction of collagen, a major structural component of the periodontal matrix, by MMP leads to gingival recession, pocket formation and tooth movement (Goulb, L B., Ryan M. E. Williams R. C., Dent. Today, 17, pp102-109).
Recent reports have also shown that MMP-1 activity is highly induced in Alzheimer's disease, and MMP-1 and MMP-3 are involved in the pathophysiology of the disease (Leake A, et al.; J. Neurosci. Lett., 291, pp201-3, 2000; Yoshiyama Y, et al., Acta Neuropathol. (Berl), 99, pp91-5, 2000).
MMPs are also responsible in solar UV radiation-induced skin damage, affecting skin tone and resiliency leading to premature aging. The symptom of that include leathery texture, wrinkles, mottled pigmentation, laxity and sallowness. Therefore, MMP inhibitors could be included in cosmetics for anti-photoaging or anti-wrinkle treatment (Hase T, et al., Br. J. Dermatol., 142, pp267-273, 2000; Fisher G. J, et al.; Photochem. Photobiol., 69, pp154-157, 1999).
Since inhibitors of MMP and angiogenesis can be applied to the treatment and prevention of many diseases, development of angiogenesis inhibitor as new therapeutics is expected. Since these inhibitors need to be administered for a long time, desirable inhibitors should not have toxic or adverse effect with good patient compliance.
Horse chestnut is a plant in Hippocastanaceae, cultivated in many countries in Europe and Asia. Triterpene saponin mixture known as aescin (also called escin) consists of diacylated tetra- and pentahydroxy-beta-amyrin compounds is a chief component of the seeds. Various flavonoids and polysaccharides are also included in the seeds. In addition to aescin, the leaves contain hydroxycoumarin such as esculin, fraxin and scopolin and flavonoids including rutin, quercitrin and isoquercitrin.
In folk medicine, the leaves have been used as a cough remedy. Japanese Horse chestnut seeds are given to patient with gastric pain, malaria, and diarrhea. Purified extract from Horse chestnut seed can be used for preparation of traditional Japanese cakes.
Horse chestnut seeds are used for treatment of symptoms in chronic venous insufficiency, because of anti-exudative and vascular tightening effects of the principal ingredient of seed extract, aescin.
Periodontal (gum) diseases, including gingivitis and periodontitis, are serious infections that, left untreated, can lead to tooth loss. Periodontal disease is a chronic bacterial infection that affects the gums and bone supporting the teeth. Periodontal disease may affect one tooth or many teeth. It begins when the bacteria in plaque causes the gums to become inflamed. In the mildest form of the disease, gingivitis, the gums redden, swell and bleed easily. Gingivitis is often caused by inadequate oral hygiene. Gingivitis is reversible with professional treatment.
Untreated gingivitis can advance to periodontitis. With time, plaque can spread and grow below the gum line. Toxins produced by the bacteria in plaque irritate the gums. The toxins stimulate a chronic inflammatory response, and the tissues and bone that support the teeth are broken down and destroyed. Gums separate from the teeth, forming spaces between the teeth and gums that become infected. As the disease progresses, the spaces deepen and more gum tissue and bone are destroyed. Eventually, teeth can become loose and may have to be removed.
Some of the main causes of periodontal disease is bacterial plaque. However, factors like the following also affect the health of the gums, such as smoking, genetics—up to 30% of the population may be genetically susceptible to gum disease. Stress is another cause.
The most common ones include the following. Gingivitis is the mildest form of periodontal disease. It causes the gums to become red, swollen, and bleed easily. There is usually little or no discomfort at this stage. Gingivitis is reversible with professional treatment and good at home oral care. Aggressive periodontitis is a form of periodontitis that occurs in patients who are otherwise clinically healthy. Common features include rapid attachment loss and bone destruction and familial aggregation. Chronic periodontitis is a form of periodontal disease resulting in inflammation within the supporting tissues of the teeth, progressive attachment and bone loss and is characterized by pocket formation and/or recession of the gingiva. It is recognized as the most frequently occurring form of periodontitis. It is prevalent in adults, but can occur at any age. Progression of attachment loss usually occurs slowly, but periods of rapid progression can occur. Also, periodontitis may be a manifestation of systemic diseases, such as diabetes. Necrotizing periodontal diseases is an infection characterized by necrosis of gingival tissues, periodontal ligament and alveolar bone. These lesions are most commonly observed in individuals with systemic conditions including, but not limited to, HIV infection, malnutrition and immunosuppression.
Periodental diseases may be treated by surgery such as pocket reduction, soft tissue grafts, regeneration procedures, crown lengthening.
The present inventors have studied the inhibitory effect of Horse chestnut extract on angiogenesis and matrix metalloproteinase and have discovered that the Horse chestnut extract could be used to inhibit a variety of angiogenesis- and MMP-dependent diseases, including early and late stage periodontal diseases.